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Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)

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Textbook of Autoinflammation

Abstract

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary disease, caused by heterozygous mutations in TNFRSF1A, which encodes for TNF-receptor 1 (TNFR1). Most of the pathogenic mutations are single-nucleotide missense variants localized in extracellular, cysteine rich domains of the receptor. The pathogenesis of TRAPS is complex and likely involves several mutually non-exclusive molecular mechanisms, however, co-expression of the mutated and wild type of the receptor is required in all cases. The proposed mechanisms include abnormal TNFR1 cleavage; increased activation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase; ligand-independent activation of mutant TNFR1; generation of mitochondrial reactive oxygen species (ROS) leading to enhanced activation of the NLRP3 inflammasome; TNFR1 misfolding and retention within the endoplasmic reticulum (ER) leading to activation of ER-associated endonuclease, inositol-requiring enzyme 1 (IRE-1) and resulting in hyper-responsiveness to lipopolysaccharide via selective degradation of microRNAs (miRs).

The majority of patients with TRAPS are symptomatic from childhood, with the median age of symptom onset reported to be about 4 years. Most patients report episodic attacks of fever, with serositis manifesting as abdominal and/or chest pain, myalgia with or without typical overlying migratory rash, arthralgia and arthritis. The minority of patients will have continuous symptoms, and many will have biochemical evidence of systemic inflammatory response even in the absence of symptoms. Prior to effective therapies, systemic amyloidosis was found in up to 15% of patients. The diagnosis of TRAPS still depends on molecular genetic analysis for conformation since formal diagnostic criteria have yet to be developed. Anti-interleukin (IL)-1 biological agents are currently the first choice of treatment for patients who require ongoing therapy.

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Abbreviations

3-MA:

3-Methyladenine

ADAM:

A disintegrin and metalloproteinase

CAPS:

Cryopyrin-associated periodic syndrome

CRD:

Cysteine-rich domains

CRP:

C-reactive protein.

DF:

Dermal fibroblasts

DMARDs:

Disease-modifying anti-rheumatic drugs

ER:

Endoplasmic reticulum

FHF:

Familial Hibernian fever

FMF:

Familial Mediterranean fever

IĸB:

I kappa beta

IKK:

I kappa B kinase

IL:

Interleukin

IRE1:

Inositol-requiring enzyme 1

JNK:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

miR:

MicroRNA

MKD:

Mevalonate kinase deficiency

mROS:

Mitochondrial ROS

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-ĸB:

Nuclear factor-κB

NLRP3:

NACHT, LRR and PYD domains-containing protein 3

NOX:

NADPH oxidases

NSAIDs:

Nonsteroidal anti-inflammatory drugs

OXPHOS:

Oxidative phosphorylation

PCR:

Polymerase chain reaction

PERK:

Protein kinase (PKR)-like endoplasmic reticulum kinase

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis

PGA:

Physician global assessment

RIP:

Receptor-interacting protein

ROS:

Reactive oxygen species

SAA:

Serum amyloid A

TACE:

TNF-alpha converting enzyme

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR1:

TNF receptor 1

UPR:

Unfolded protein response

XBP1:

X-box binding protein 1

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Authors and Affiliations

  1. Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, UK

    Sinisa Savic

  2. Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), St James’s University Hospital, Leeds, UK

    Sinisa Savic & Michael F. McDermott

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  1. Sinisa Savic
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  2. Michael F. McDermott
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Correspondence to Sinisa Savic .

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Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

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Savic, S., McDermott, M.F. (2019). Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS). In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_18

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